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Objective Studies have shown that dipeptidyl peptidase-4 (DPP-4) inhibitors have anti-inflammatory effects. Soluble DPP-4 (sDPP-4) has been considered as an adipokine of which actions need to be further characterized. Methods We investigated the pro-inflammatory actions of sDPP-4 and the anti-inflammatory effects of DPP-4 inhibition, using vildagliptin, as an enzymatic inhibitor, and mannose-6-phosphate (M6P) as a competitive binding inhibitor. Results In lipopolysaccharide (LPS)-stimulated RAW264.7 cells, vildagliptin suppressed the increased expression of inducible nitric oxide synthase (iNOS) and phosphorylated JNK (pJNK), activation of the NF-κB pathway, and the resultant NO and proinflammatory cytokine production. Although sDPP-4 alone did not affect the protein level of iNOS or pJNK or the production of NO in RAW264.7 cells, it did amplify iNOS expression, NO responses, and proinflammatory cytokine production in LPS-stimulated RAW264 cells. As a probable mechanism, we found that sDPP-4 caused dose-dependent increases in the expression levels of toll-like receptor 4 (TLR4) and TLR2 in RAW264.7 cells, and that these alterations were inhibited by vildagliptin, M6P, or bisindolylmaleimide II, a protein kinase C inhibitor. Either vildagliptin or M6P suppressed iNOS expression and NO and cytokine production in LPS + DPP-4-co-stimulated macrophages, while combined treatment of the co-stimulated cells with both agents had increased anti-inflammatory effects compared with either treatment alone. Intravenous injection of sDPP-4 to C57BL/6J mice increased the expression of both TLRs in kidney and white adipose tissues. Conclusion Our findings suggest that sDPP-4 enhances inflammatory actions via TLR pathway, while DPP-4 inhibition with either an enzymatic or binding inhibitor has anti-inflammatory effects.

Guggulsterone (GS) is a phytosterol that has been used to treat inflammatory diseases such as colitis, obesity, and thrombosis. Although many previous studies have examined activities of GS, the effect of GS on lipopolysaccharide (LPS)-induced inflammatory responses in mouse inner medullary collecting duct-3 (mIMCD-3) cells have not been examined. Therefore, here, we investigated the anti-inflammatory action of GS on mIMCD-3 cells exposed to LPS. LPS treatment on mIMCD-3 cells produced pro-inflammatory molecules such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) significantly; however, GS treatment significantly inhibited the production of pro-inflammatory molecules. In addition, GS inhibited the degradation of Iκ-Bα and translocation of NF-κB on mIMCD-3 cells. These results suggest that GS could inhibit inflammatory responses in collecting duct cells which could contribute to kidney injury during systemic infection.

Non-alcoholic fatty liver disease (NAFLD) is characterized by the hepatic manifestation of metabolic syndrome and is the leading cause of chronic liver disease. Steatohepatitis plays a critical role in the process resulting in liver fibrosis and cirrhosis. Puerarin is a herbal product widely used in Asia, and is believed to have therapeutic benefits for alleviating the symptoms of steatohepatitis. The present study was designed to investigate the effects and mechanisms of action of puerarin in reducing lipid accumulation in oleic acid (OA)-treated HepG2 cells. Hepatocytes were treated with OA with or without puerarin to observe lipid accumulation by Oil Red O staining. We also examined hepatic lipid contents (e.g., triacylglycerol and cholesterol) following treatment with puerarin. Western blot analysis and reverse transcription-polymerase chain reaction (RT-PCR) were used to measure sterol regulatory element binding protein (SREBP)-1, fatty acid synthase (FAS), peroxisome proliferator-activated receptor α (PPARα) and adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) protein and mRNA expression, respectively. Our results revealed that puerarin suppressed OA-induced lipid accumulation, and reduced the triacylglycerol and cholesterol levels. Furthermore, puerarin decreased the expression levels of lipogenic enzymes, such as FAS and SREBPs, and increased the expression levels of PPARα, which are critical regulators of hepatic lipid metabolism through the AMPK signaling pathway. These results indicate that puerarin has the same ability to activate AMPK, and reduce SREBP-1 and FAS expression, thus inhibiting hepatic lipogenesis and increasing hepatic antioxidant activity. We found that puerarin exerted a regulatory effect on lipid accumulation by decreasing lipogenesis in hepatocytes. Therefore, puerarin extract may have therapeutic benefits in the treatment of fatty liver and lipid-related metabolic disorders.

Sodium butyrate (SB) has various metabolic actions. However, its effect on dipeptidyl peptidase 4 (DPP-4) needs to be studied further. We aimed to evaluate the metabolic actions of SB, considering its physiologically relevant concentration. We evaluated the effect of SB on regulation of DPP-4 and its other metabolic actions, both in vitro (HepG2 cells and mouse mesangial cells) and in vivo (high fat diet [HFD]-induced obese mice). Ten-week HFD-induced obese C57BL/6J mice were subjected to SB treatment by adding SB to HFD which was maintained for an additional 16 weeks. In HepG2 cells, SB suppressed DPP-4 activity and expression at sub-molar concentrations, whereas it increased DPP-4 activity at a concentration of 1,000 µM. In HFD-induced obese mice, SB decreased blood glucose, serum levels of insulin and IL-1β, and DPP-4 activity, and suppressed the increase in body weight. On the contrary, various tissues including liver, kidney, and peripheral blood cells showed variable responses of DPP-4 to SB. Especially in the kidney, although DPP-4 activity was decreased by SB in HFD-induced obese mice, it caused an increase in mRNA expression of TNF-α, IL-6, and IL-1β. The pro-inflammatory actions of SB in the kidney of HFD-induced obese mice were recapitulated by cultured mesangial cell experiments, in which SB stimulated the secretion of several cytokines from cells. Our results showed that SB has differential actions according to its treatment dose and the type of cells and tissues. Thus, further studies are required to evaluate its therapeutic relevance in metabolic diseases including diabetes and obesity.

The root of Polygala tenuifolia Willd. (Polygalaceae) is well known for its use in the treatment of neurasthenia, amnesia, and inflammation. In this study, we isolated phenyl propanoid type metabolite tenuifoliside A, one of the phenylpropanoids from P. tenuifolia, and investigated its anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated RAW264.7 and murine peritoneal macrophages. The results showed that tenuifoliside A inhibited the production of nitric oxide (NO), inducible nitric oxide synthase (iNOS), prostaglandin E2 (PG E2), and cyclooxygenase (COX)-2. In addition, tenuifoliside A suppressed the production of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β. We also evaluated the effects of tenuifoliside A on the activation of nuclear factor-kappaB (NF-κB). Tenuifoliside A inhibited the translocation of the NF-κB subunit p65 into the nucleus by interrupting the phosphorylation and degradation of inhibitor kappa B (IκB)-α in LPS-stimulated murine peritoneal macrophages. Moreover, we confirmed that the suppression of the inflammatory process by tenuifoliside A was mediated through the mitogen-activated protein kinases (MAPKs) pathway based on the fact that tenuifoliside A significantly decreased p-c-Jun N-terminal kinase (p-JNK) protein expression in LPS-stimulated murine peritoneal macrophages. Taken together, the anti-inflammatory effects of tenuifoliside A were mediated by the inhibition of the NF-κB and MAPK pathways. This study is the first report on the anti-inflammatory effects of tenuifoliside A, and the strong anti-inflammatory effects of tenuifoliside A provide potential compound to be developed as therapeutic for inflammatory diseases.

Saussurea pulchella (Asteraceae) is widely distributed in Korea and has been used in Korean folk medicine for the treatment of inflammation, hypertension, hepatitis, and arthritis. Pulchellamin G is an amino acid-sesquiterpene lactone conjugate isolated from S. pulchella. In the present study, we focused on the anti-inflammatory effect of pulchellamin G, which acts by inducing the expression of heme oxygenase (HO)-1. HO-1 plays important roles in cytoprotection since it has antioxidant, anti-inflammatory, antiproliferative, and antiapoptotic properties. Pulchellamin G inhibited the mRNA and protein expression of inducible nitric oxide synthase (iNOS), iNOS-derived nitric oxide (NO), and cyclooxygenase (COX)-2 and COX-derived prostaglandin E2 (PGE2) production in lipopolysaccharide (LPS)-stimulated murine peritoneal macrophages. The compound also reduced tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) production and suppressed the phosphorylation and degradation of IκB-α and nuclear translocation of p65 in murine peritoneal macrophages in response to LPS stimulus. The inhibitory effects of pulchellamin G on nuclear factor kappa B (NF-κB) translocation was impaired by co-treatment of the cells with HO activity inhibitor tin protoporphyrin (SnPP). By using SnPP, we verified that the inhibitory effects of pulchellamin G on the pro-inflammatory mediators NO, PGE2, TNF-α, and IL-1β are associated with induction of HO-1 expression. Our data suggest that pulchellamin G might have potent therapeutic effects and it should be considered in the development of treatments for various inflammatory diseases.

We have previously reported that bee venom (BV) has a protective role against acute pancreatitis (AP). However, the effects of apamin, the major compound of BV, on AP have not been determined. The aim of this study was to evaluate the effects of apamin on cerulein-induced AP.AP was induced via intraperitoneal injection of supramaximal concentrations of the stable cholecystokinin analogue cerulein (50 μg/kg) every hour for 6 times. In the apamin treatment group, apamin was administered subcutaneously (10, 50, or 100 μg/kg) at both 18 and 1 h before the first cerulein injection. The mice were sacrificed at 6 h after the final cerulein injection. Blood samples were obtained to determine serum amylase and lipase levels, as well as cytokine production. The pancreas and lung were rapidly removed for morphologic and histological examination, myeloperoxidase (MPO) assay, and real-time reverse transcription-polymerase chain reaction. Furthermore, we isolated the pancreatic acinar cells to specify the role of apamin in AP.Pre-treatment with apamin inhibited histological damage, pancreatic weight/body weight ratio, serum level of amylase and lipase, MPO activity, and cytokine production. In addition, apamin treatment significantly inhibited cerulein-induced pancreatic acinar cell death. Furthermore, apamin treatment inhibited the cerulein-induced activation of c-Jun NH2-terminal kinases (JNK).These results could suggest that apamin could protect against AP by inhibition of JNK activation.

Amiodarone is a highly effective antiarrhythmic agent. It is commonly used to treat ventricular and supraventricular arrhythmias. However, amiodarone has been found to be associated with a variety of adverse effects. Amiodarone causes toxicity to organs such as lung, gastrointestinal tract, liver, eye, thyroid gland, skin, and neuromuscular system. Among these side effects, pulmonary toxicity is one of the most serious ones. The prevalence of amiodarone-induced pulmonary toxicity is not known precisely, but recent studies have reported that incidence rates range from 1% to 13%. The risk factors associated with the development of pulmonary toxicity are age, duration of treatment, cumulative dosage, history of cardiothoracic surgery, and use of high oxygen mixture. Amiodarone use has been rarely related to development of acute respiratory distress syndrome (ARDS), which is often in association with surgery or pulmonary angiography. We experienced a case of amiodarone-induced ARDS which developed after an increase of amiodarone dosage.

KCHO-1 is a novel product comprised of 30% ethanol extracts obtained from nine medical herbs, which are commonly used in traditional Korean and Chinese medicine. The nine herbs include Curcuma longa, Salvia miltiorrhiza, Gastrodia elata, Chaenomeles sinensis, Polygala tenuifolia, Paeonia japonica, Glycyrrhiza uralensis, Atractylodes japonica and processed Aconitum carmichaeli. Recent studies have reported the beneficial effects of these herbs. The present study aimed to investigate the direct neuroprotective effects of KCHO‑1 on HT22 mouse hippocampal cells, and to determine the possible underlying mechanisms. KCHO‑1 significantly suppressed glutamate‑ and hydrogen peroxide (H2O2)‑induced cell damage, and reactive oxygen species generation. In addition, KCHO‑1 increased the mRNA and protein expression levels of heme oxygenase (HO)‑1. Tin protoporphyrin, which is an inhibitor of HO activity, partially suppressed the effects of KCHO‑1. Furthermore, KCHO‑1 significantly upregulated nuclear factor erythroid‑derived 2‑related factor‑2 (Nrf2) nuclear translocation. Extracellular signal‑regulated kinase (ERK) activation also appeared to be associated with KCHO‑1‑induced HO‑1 expression, since the ERK inhibitor PD98059 suppressed HO‑1 expression and prevented KCHO‑1‑induced cytoprotection. The results of the present study suggested that KCHO‑1 may effectively prevent glutamate‑ or H2O2‑induced oxidative damage via Nrf2/ERK mitogen‑activated protein kinase‑dependent HO‑1 expression. These data suggest that KCHO‑1 may be useful for the treatment of neurodegenerative diseases.

Metabolic syndrome is a medical disorder characterized by obesity, hyperglycemia, dyslipidemia, and hypertension. Black currant (Ribes nigrum L, BC) has been used for horticultural crop in europe n...

The spontaneously hypertensive rat (SHR) has an enhanced tubuloglomerular feedback (TGF) and a diminished buffering by juxtaglomerular apparatus (JGA)-derived NO. We examined the hypothesis that these effects are due to decreases in nitric oxide synthase (NOS) expression or limited availability of l-arginine or tetrahydrobiopterin (BH4). SHR had significantly ( P < 0.05) greater mRNA abundance (by RT-PCR) or protein (by Western analysis) for neuronal NOS (nNOS, or type I) and endothelial cell NOS (ecNOS, or type III) in renal cortex or isolated glomeruli, respectively. There was prominent expression of ecNOS in glomerular endothelium and nNOS in macula densa. Maximal TGF responses, assessed from changes in proximal stop-flow pressure during orthograde loop of Henle (LH) perfusion, were greater in SHR [Wistar-Kyoto (WKY), 8.1 ± 0.3 ( n = 46) vs. SHR, 10.3 ± 0.3 mmHg ( n = 57); P < 0.001]. Unlike WKY, TGF responses of SHR were unresponsive to microperfusion of the nNOS inhibitor, 7-nitroindazole (7-NI, 10−4M) [WKY, 9.5 ± 0.5 to 13.2 ± 0.7 ( n = 13, P < 0.001) vs. SHR, 11.8 ± 0.7 to 12.5 ± 0.6 mmHg ( n = 19, not significant)], or tol-arginine (10−3M) [WKY, 7.7 ± 0.8 to 6.3 ± 0.4 ( n = 10, P < 0.05) vs. SHR, 10.4 ± 0.7 to 10.6 ± 0.7 mmHg ( n = 10, not significant)]. Neither BH4(10−4M) nor sepiapterin (10−4M), its stable precursor, modified TGF responses in WKY or in SHR, nor did they restore a response to microperfusion of 7-NI in SHR. In conclusion, there is a diminished role for NO from nNOS in blunting of TGF in SHR which cannot be ascribed to limited NOS expression or availability of substrate or BH4.

Objectives The present study was aimed at exploring whether the pathogenesis of hypertension is related with an altered expression of nitric oxide synthase (NOS) isozymes, i.e., bNOS, iNOS and ecNOS. Method By Western blot analysis, the expression of NOS isozymes were determined in the kidney isolated from spontaneously hypertensive rats (SHR) and their normotensive control, Wistar-Kyoto rats (WKY). The NOx (nitrite/nitrate) contents were also determined in the kidney and plasma. Results The plasma NOx was significantly increased in SHR compared with that in WKY. The basal level of NOx was higher in the medulla and cortex of the kidney in SHR compared with that in WKY rat. bNOS proteins were expressed higher in the outer medulla and cortex, and iNOS proteins were higher in the inner medulla, outer medulla and cortex in SHR. ecNOS expression did not significantly differ between the SHR and WKY. Conclusions These results indicate that the NO generation may not be impaired, but rather increased. It is likely that the increased expression of NOS isozymes is a counter-reactive phenomenon secondary to the increased blood pressure in this model of hypertension.

We describe a 64-year-old male patient with panhypopituitarism who experienced polymorphic ventricular tachycardia (VT) associated with long QT intervals. The panhypopituitarism developed as a sequelae of radiation therapy administered 20 years prior to his current presentation and was recently aggravated by urinary tract infection with sepsis. In this case, polymorphic VT was resistant to conventional therapy (including magnesium infusion), and QT prolongation and T wave inversion were normalized after the administration of steroid and thyroid hormones. Thyroid hormone is generally known to be associated with torsades de pointes (TdP), but steroid or other hormones may also provoke TdP. Hormonal disorders should be considered as a cause of polymorphic VT with long QT intervals. Some arrhythmias can be life-threatening, and they can be prevented with supplementation of the insufficient hormone.

Selective intestinal decontamination (SID) with norfloxacin has been widely used for the prophylaxis of spontaneous bacterial peritonitis (SBP) because of a high recurrence rate and preventive effect of SID for SBP. However, it does select resistant gut flora and may lead to SBP caused by unusual pathogens such as quinolone-resistant gram-negative bacilli or gram-positive cocci. Enterococcus hirae is known to cause infections mainly in animals, but is rarely encountered in humans. We report the first case of SBP by E. hirae in a cirrhotic patient who have previously received an oral administration of norfloxacin against SBP caused by Klebsiella pneumoniae and presented in septic shock.

Sauchinone, a biologically active lignan isolated from the roots of Saururus chinensis (LOUR.) BAILL. (Saururaceae), is reported to exert a variety of biological activities, such as hepatoprotective, anti-inflammatory actions and inhibitory effects on bone resorption. In this study, we investigated the effect of sauchinone in suppressing cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, leading to a reduction in COX-2-derived prostaglandin E(2) (PGE(2)) and iNOS-derived nitric oxide (NO) production in lipopolysaccharide (LPS) stimulated RAW264.7 macrophages. Present study also demonstrates the effects of sauchinone in inducing heme oxygenase-1 (HO-1) expression and an increase in heme oxygenase (HO) activity in RAW264.7 macrophages. The effects of sauchinone on LPS-induced PGE(2), NO, tumor necrosis factor-α (TNF-α) and interlukine-1β (IL-1β) production were partially reversed by the HO-1 inhibitor Tin protoporphyrin was also seen in this study. In addition, we found that treatment with extracellular signal-regulated kinase (ERK) inhibitor (PD98059) reduced sauchinone-induced HO-1 expression. Sauchinone also increased ERK phosphorylation. These results suggest that sauchinone inhibits pro-inflammatory mediators through expression of anti-inflammatory HO-1 via ERK pathway.

AHNAK is a giant protein of approximately 700 kDa identified in human neuroblastomas and skin epithelial cells. Recently, we found that AHNAK knock-out (AHNAK(-/-)) mice have a strong resistance to high-fat diet-induced obesity. In this study, we applied (1)H NMR-based metabolomics with multivariate statistical analysis to compare the altered metabolic patterns detected in urine from high-fat diet (HFD) fed wild-type and AHNAK(-/-) mice and investigate the mechanisms underlying the resistance to high-fat diet-induced obesity in AHNAK(-/-) mice. In global profiling, principal components analysis showed a clear separation between the chow diet and HFD groups; wild-type and AHNAK(-/-) mice were more distinctly separated in the HFD group compared to the chow diet group. Based on target profiling, the urinary metabolites of HFD-fed AHNAK(-/-) mice gave higher levels of methionine, putrescine, tartrate, urocanate, sucrose, glucose, threonine, and 3-hydroxyisovalerate. Furthermore, two-way ANOVAs indicated that diet type, genetic type, and their interaction (gene × diet) affect the metabolite changes differently. Most metabolites were affected by diet type, and putrescine, threonine, urocanate, and tartrate were also affected by genetic type. In addition, cis-aconitate, succinate, glycine, histidine, methylamine (MA), phenylacetylglycine (PAG), methionine, putrescine, uroconate, and tartrate showed interaction effects. Through the pattern changes in urinary metabolites of HFD-fed AHNAK(-/-) mice, our data suggest that the strong resistance to HFD-induced obesity in AHNAK(-/-) mice comes from perturbations of amino acids, such as methionine, putrescine, threonine, and histidine, which are related to fat metabolism. The changes in metabolites affected by microflora such as PAG and MA were also observed. In addition, resistance to obesity in HFD-fed AHNAK(-/-) mice was not related to an activated tricarboxylic acid cycle. These findings demonstrate that (1)H NMR-based metabolic profiling of urine is suitable for elucidating possible biological pathways perturbed by functional loss of AHNAK on HFD feeding and could elucidate the mechanism underlying the resistance to high-fat diet-induced obesity in AHNAK(-/-) mice.

An altered role of AQP2 water channels in DOCA-salt hypertension was investigated. DOCA-salt hypertension was induced in rats. Control groups were either treated with DOCA alone or subjected to a high-salt intake without DOCA. Four weeks after inducing the hypertension, AQP2 expression and shuttling were determined in the kidney. Adenylate cyclase activity was also determined to examine the upstream affecting the AQP2 system. The AVP-evoked cAMP generation in the cortex and outer medulla was augmented following the treatment with DOCA either alone or combined with high-salt intake. Accordingly, the expression and shuttling of AQP2 proteins were increased in the cortex and outer medulla. These findings suggest that DOCA enhances cAMP generation and expression/shuttling of AQP2 water channels in the kidney, which may be causally related with the development of hypertension.

Caplan’s syndrome is characterized by multiple small distinct nodules with progressive massive fibrosis and rheumatic arthritis in pneumoconiosis. Although pleural effusions occur infrequently as an extra-articular manifestation, pleuritis can develop without joint involvement in patients with rheumatoid arthritis. We treated an 81-year-old man who had been diagnosed with silicosis with progressive massive fibrosis. He suffered from progressive dyspnea, and chest computed tomography (CT) and echocardiography revealed pleural and pericardial effusions. We speculated that the multiple serositis was related to a rheumatic disorder because the rheumatic factor was elevated in both the pleural and pericardial effusions. After corticosteroid treatment, the serositis improved. We suggest that this case is an atypical pattern of Caplan’s syndrome presenting as serositis without arthritis. Rheumatoid serositis should be considered as the cause of pleural or pericardial effusions in patients with pneumoconiosis. (Korean J Med 2013;84:428-432)

Cronkhite-Cadana syndrome is a rare non-familial disease. This syndrome is characterized by multiple hamartomatous polyps on the entire gastrointestinal tract except esophagus, nail dystrophy, alopecia and hyperpigmentation. Taste disturbance, abdominal pain, diarrhea and weight loss are common symptoms of it. The pathogenesis and causes of Cronkhite-Canada syndrome remain unknown until now. Although various treatment strategies including steroid therapy have been tried, their prognosis is poor. We report a 68 years old man who were diagnosed Cronkhite-Canada syndrome with esophageal candidiasis. After using combination of steroids and anti-fungal drugs, both Cronkhite-Canada syndrome and esophageal candidiasis were cured. (Korean J Helicobacter Up Gastrointest Res 2012;12:183-187)